Stress is a major factor that interacts with genetic makeup & drug experience to determine vulnerability to addiction & relapse. The degree of behavioral control that an organism (rat to human) has over a stressor is arguably the most potent modulator of the behavioral & physiological impact of stressors yet discovered, & a lack of control over stressors has been found to be a predisposing factor to addiction at the human level. The research to be conducted focuses on the role of behavioral control & lack of control over stress in determining the impact of stress on behavioral and neurochemical responses tro drugs of abuse. Uncontrollable, relative to controllable stress, has been shown to sensitize serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN) so that for a period of days these neurons respond to input in an exaggerated fashion, releasing excessive amounts of 5-HT in projection regions. Research conducted during the past grant period has shown that uncontrollable stress potentiates morphine-induced conditioned place preference, psychomotor responses, nucleus accumbens dopamine release, and plasma corticosterone (CORT) for a period of many days, whereas exactly equal controllable stress does not. Furthermore, uncontrollable stress-induced sensitization of DRN 5-HT neurons & release of excessive 5-HT was shown to be necessary to produce these phenomena, as was the potentiated CORT increase. Moreover, preliminary data suggest that it is 5-HT released in the medial prefrontal cortex (mPFC) that is critical to the augmented behavioral and neurochemical responses to morphine produced by prior uncontrollable stress. The Aims of the new proposed work are to determine a) whether 5-HT and CORT act within the mPFC to produce exaggerated responses to morphine & how this occurs; b) whether uncontrollable stress would potentiate behavioral & neurochemical responses to drugs other than opiates if they are experienced in a way that activates DRN 5-HT neurons; and c) how control over stress prevents stressors from increasing reactivity to drugs of abuse & confers resilience. This research should provide insights into the neural mechanisms that produce vulnerability & resilience to the modulatory effects of stress on reactions to drugs of abuse & suggest methods to combat the deleterious effects of stress. [unreadable] [unreadable] [unreadable]